Elderly patients who suffer traumatic brain injury (TBI) have increased mortality and survivors have a poorer prognosis than young or middle aged adults who suffer comparable injuries. We have demonstrated that the aging brain is in a hyperinflammatory state before any injury, that the inflammatory response after brain injury is exaggerated, and that both edema and blood brain barrier disruption are increased after TBI in the aged brain. The proposed experiments test the specific hypothesis that increased matrix metalloproteinase (MMP) activity worsens blood brain barrier disruption and causes increased edema after TBI in the aged brain, leading to increased death of neurons and poor behavioral recovery. An interdisciplinary research team including a neuroscientist with expertise in molecular and behavioral neuroscience and neuroanatomy, an MRI physicist, and an expert in pharmacokinetics will test this hypothesis using the controlled cortical impact (CCI) model of TBI in mice. The specific aims are 1) to determine whether CCI results in increased MMP-2 and MMP-9 activity in aged mice, 2) to determine whether blood brain barrier disruption, edema, and neuron death are greater after CCI in aged mice leading to poor behavioral recovery, and 3) to determine whether reducing MMP activity improves outcomes. The overall goal of these studies is to provide a rationale for specific treatments to improve outcomes of TBI in the elderly and to test effectiveness of treatments based on this rationale. PUBLIC HEALTH RELEVANCE: Elderly patients who suffer traumatic brain injury have increased mortality, and survivors have a poorer prognosis, than younger adults who suffer comparable injuries. The goal of this research program is to understand the reason for these poor outcomes and to provide new treatment strategies using an animal model.